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EP1572653B1 - Heteroarylcycloalkymethyl amines saturees et insaturees en tant qu'antidepresseurs - Google Patents

Heteroarylcycloalkymethyl amines saturees et insaturees en tant qu'antidepresseurs Download PDF

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Publication number
EP1572653B1
EP1572653B1 EP03815065A EP03815065A EP1572653B1 EP 1572653 B1 EP1572653 B1 EP 1572653B1 EP 03815065 A EP03815065 A EP 03815065A EP 03815065 A EP03815065 A EP 03815065A EP 1572653 B1 EP1572653 B1 EP 1572653B1
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Prior art keywords
pyridin
amine
dimethyl
enylmethyl
hydrochloride
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German (de)
English (en)
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EP1572653A1 (fr
Inventor
Petra Bloms-Funke
Claudia Pütz
Ivars Graudums
Achim Kless
Carsten Griebel
Hagen-Heinrich Hennies
Dagmar Kaulartz
Sabine Reinardy
Derek Saunders
Klaus Schiene
Werner Englberger
Oswald Zimmer
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority to CY20081100091T priority patent/CY1107867T1/el
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • the present invention relates to saturated and unsaturated heteroarylcycloalkylmethyl amines, processes for their preparation, medicaments containing these compounds and the use of saturated and unsaturated heteroarylcycloalkylmethyl amines for the preparation of medicaments and methods for the treatment of depression and / or pain.
  • Depression is a disorder of affectivity, in which a depressive syndrome is in the foreground, where depressive is associated with mood or sad mood.
  • Depressive disorders include unipolar light depression, dysthimia, melancholy, bipolar depression, severe depression with or without delusion, moderate depression, (bipolar disorder I, mania and severe depression, bipolar disorder II, hypomania and major depression, cyclothymic personality disorders, hypomania and mild Depression).
  • antidepressants are widely used whose antidepressant action is based on a reuptake inhibition of the monoamines norepinephrine (NA) or serotonin (5-HT) ( Pacher, P., Kohegyi, E., Kecskemeti, V., Furst, S., Current Medicinal Chemistry 2001, 8, 89-100 ).
  • Monoamine reuptake inhibitors are also used to treat anxiety disorders ( Goddard, AW, Coplan, JD, Gorman, JM, Charney, DS, In: Neurobiology of mental illness, Charney, DS, Nestler, EJ, Bunney, BS (ed.), Oxford University Press, New York, 1999, p. 548-563 ).
  • Anxiety disorders are divided into Generalized Anxiety Disorders, Panic Attacks, Forced Syndromes, Social Anxiety Disorders, Simple Phobias, Agoraphobia, Posttraumatic Stress Disorder (PTSD).
  • reuptake inhibitors of norepinephrine and serotonin also lead to one independent analgesic effect by activating descending pain barriers at the level of the spinal cord.
  • Monoamine reuptake inhibitors are used clinically for monotherapy as well as adjuvants for the treatment of chronic pain (including neuropathic pain) (Sindrup, in: Yaksh, TL, et al., Anesthesia. Biological foundations. Philadelphia: Lippincott Raven, 1997, 987-997 ).
  • Classic opiates are effective in the treatment of severe to severe pain, but in neuropathic pain their effectiveness is not satisfactory.
  • the use of the monoamine reuptake inhibitors is limited by side effects, e.g. Accommodation disorders, serotonin syndrome or QT prolongations restricted.
  • An object underlying the invention was to provide new compounds which are suitable for the treatment of depression, anxiety disorders or pain.
  • these compounds should minimize the side effects of monoamine reuptake inhibitors, e.g. Accommodation disorders, serotonin syndrome or QT prolongations.
  • Other tasks included new drugs for the treatment of anxiety, urinary incontinence, fibromyalgia, eating disorders, bulimia, hyperactivity, drug addiction, addiction and withdrawal, trichotillomania, Tourette's syndrome, skin conditions such as postherpetic neuralgia and pruritus, psychosis, memory disorders, cognitive disorders and morbidity To provide Alzheimer's.
  • saturated and unsaturated heteroarylcycloalkyl-methylamines of the following general formula I inhibit the reuptake of norepinephrine and / or serotonin.
  • the substances have pronounced antidepressant, anxiolytic and antinociceptive effects and are therefore used to treat Depression, anxiety disorders and pain suitable.
  • the compounds of the invention have potential for the treatment of chronic pain conditions associated with depressive moods or anxiety disorders.
  • the substances are suitable for the treatment of migraine, urinary incontinence, fibromyalgia, eating disorders, bulimia, hyperactivity, drug addiction, addiction and withdrawal, trichotillomania, Tourette's syndrome, skin diseases such as postherpetic neuralgia and pruritus, psychosis, memory disorders, cognitive disorders and Alzheimer's disease ,
  • substituted in the context of this invention means the substitution of at least one hydrogen radical by F, Cl, Br, I, CN, CF 3 , NO 2 , C 1 -C 10 -alkyl, C C 2 -C 10 -alkenyl or C 3 -C 10 -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted by F, Cl, Br, I, NH 2 , SH or OH, OCH 3 or unsubstituted; C 3 -C 7 -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted by F, Cl, Br, I, NH 2 , SH or OH, OCH 3 or unsubstituted, or a corresponding heterocycle in which a C atom in the Ring replaced by S.
  • R 5 selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2- C 10 alkynyl, in each case branched or unbranched, mono- or polysubstituted by F, Cl, Br, I, NH 2, SH or OH , OCH 3 or unsubstituted; OR 6 , OC (O) R 6 , OC (S) R 6 , C (O) R 6 , C (O) OR 6 , C (S) R 6 , C (S) OR 6 , SR 6 , S ( O) R 6 or S (O 2 ) R 6 , wherein R 6 is selected from H, C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl or C 2 -C 10 -alkynyl, in each case branched or unbranched, simple or polysubstituted by F, Cl, Br, I, NH 2 , SH or OH
  • R 8 and R 9 are independently selected from H, C 1 -C 18 -alkyl, C 2 -C 18 -alkenyl or C 3 -C 18 -alkynyl, in each case branched or unbranched, monosubstituted or polysubstituted by F, Cl, Br, I, NH 2 , SH or OH , OCH 3 or unsubstituted; C 3 -C 7 -cycloalkyl, saturated or unsaturated, monosubstituted or polysubstituted by F, Cl, Br, I, NH 2 , SH or OH, OCH 3 or unsubstituted, or a corresponding heterocycle in which a C atom in the Ring replaced by S, O or NR 10 , with R 10 selected from H, C 1 -C 10 -alkyl, C 2 -C 10 -alken
  • R 1 and R 2 are independently selected from H, C 1 -C 10 -alkyl, alkylaryl, saturated or unsaturated, simple or polysubstituted by F, Cl, Br, I, NH 2 , SH or OH, OCH 3 or unsubstituted; Alkyl heteroaryl, saturated or unsaturated, monosubstituted or polysubstituted by F, Cl, Br, I, NH 2 , SH or OH, OCH 3 or unsubstituted, or R 1 and R 2 together represent a C 3 -C 7 cycloalkyl, saturated or unsaturated, mono- or polysubstituted by F, Cl, Br, I, NH 2 . SH or OH, OCH 3 or unsubstituted form, and the group G is unsubstituted or substituted by Cl, Br or OR 6 , wherein R 6 is H or C 1 -C 10 -alkyl, alkylaryl, saturated or unsaturated, simple or polysub
  • C 1 -C 10 -alkyl in the context of this invention means hydrocarbons having 1 to 10 carbon atoms. Examples are methyl, ethyl, propyl, isopropyl, n-butane, sec. Butyl, tert. Butyl, n-pentane, neopentyl, n-butane, sec. Butyl, tert. Butyl, n-hexane, n-heptane, n-octane, n-nonane, n-decane unsubstituted or mono- or polysubstituted called.
  • C 2 -C 10 -alkenyl or "C 2 -C 10 -alkynyl” in the context of this invention means hydrocarbons having 2 to 10 carbon atoms. Examples which may be mentioned are ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl unsubstituted or mono- or polysubstituted or ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl unsubstituted or mono- or polysubstituted.
  • C 3 -C 7 -cycloalkyl in the context of this invention means cyclic hydrocarbons having 3 to 7 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl or cycloheptenyl may be saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted.
  • a "corresponding heterocycle” is understood as meaning a C 3 -C 7 -cycloalkyl in which at least one C atom in the ring is replaced by S, O or N.
  • aryl in the context of this invention means phenyls or naphthyls.
  • alkylaryl in the context of this invention means aryls substituted with C 1 -C 10 -alkylene, where the terms aryl and alkyl have the same meaning as above.
  • heteroaryl in the context of this invention means 5- or 6-membered, optionally provided with a fused aryl system, aromatic compounds containing one or two heteroatoms from the group of nitrogen, oxygen and / or sulfur.
  • Furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline are examples in this group.
  • salt formed with a physiologically acceptable acid means salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
  • Another object of the present invention is a process for the preparation of saturated and unsaturated heteroarylcycloalkylmethyl amines of the above general formula I.
  • a in the following general formula II has the meaning CH 2 , O. S, SO or SO 2 .
  • Heteroarylcycloalkylmethylamine of the general formula I are prepared by first reacting cycloalkanones of the general formula II with immonium salts of the formula III or with paraformaldehyde and an amine of the formula IV .
  • R 10 has an R 1 analogous meaning
  • R 11 is an R 2 analogous meaning.
  • the reaction of the Mannich bases with an organolithium compound of the formula V in which Z is Li and V has a meaning corresponding to G can be carried out in an aliphatic ether, for example diethyl ether and / or tetrahydrofuran at temperatures between -70 ° C and 60 ° C.
  • R 10 or R 11 or both are simultaneously hydrogen
  • compounds of the general formula III or IV are used in the Mannich reaction, in which R 10 or R 11 or R 10 and R 11 represent a benzyl radical .
  • This is at a suitable point of the reaction sequence by reacting the corresponding compounds with catalytically activated hydrogen, wherein platinum or palladium, absorbed on a support material such as activated carbon, serve as a catalyst removed.
  • Lithalumorganische compounds of formula V in which Z is Li and V has a meaning corresponding to G can be prepared by reacting halogen compounds of the formula VI in which A is Cl, Br or I and V has a meaning corresponding to G, for example n- Butyllithium / hexane solution obtained by halogen-lithium exchange.
  • This gives first products of the general formula VII in which R 10 has an analogous meaning R 1 , R 11 has an analogous meaning R 2 and V has a meaning corresponding to G.
  • R 10 has an analogous meaning R 1
  • R 11 has an analogous meaning R 2
  • V has a meaning corresponding to G.
  • OH-SH and NH 2 groups can undergo undesirable side reactions. It is therefore preferred to provide these with protective groups or replace in the case of NH 2 by NO 2 and in the last reaction step to split off the protecting group, or to reduce the NO 2 group.
  • Another object of the invention is Therefore, a modification of the method described above, in which at least one OH group contained in formula I by a OSi (Ph) 2 tert.but.
  • At least one SH group by a Sp-methoxybenzyl group and / or at least one NH 2 Group is replaced by a NO 2 group and after completion of the entire reaction sequence of an OSi (Ph) 2 tert.but.-group with tetrabutylammonium fluoride in tetrahydrofuran and / or at least one p-methoxybenzyl group with a metal amine preferably cleaved and / or sodium at least a NO 2 group is reduced to NH 2 .
  • carboxylic acid or thlocarboxylic acid groups may not be stable, so that it is preferable to react their methyl esters and the product of the BuLi reaction in the last reaction step with KOH solution or NaOH solution in To saponify methanol at 40 ° C - 60 ° C.
  • Another object of the invention is therefore a modification of the method described above, in which after the BuLi reaction, a process product having at least one C (O) OCH 3 and / or C (S) OCH 3 group with KOH solution or NaOH solution in methanol at 40 ° C - 60 ° C is saponified.
  • the purification of the compounds obtained in the individual reaction sequences is carried out by crystallization or column chromatography.
  • the compounds of the formula I can be combined with physiologically tolerated acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and / or aspartic acid in a manner known per se Transfer salts.
  • physiologically tolerated acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and / or aspartic acid in a manner known per se Transfer salts.
  • the salt formation is carried out in a solvent such as diisopropyl ether, alkyl acetate, acetone and / or 2-butanone.
  • the saturated and unsaturated heteroarylcyctoalkylmethyl amines of the general formula I according to the invention are toxicologically harmless and are therefore suitable as pharmaceutical active ingredients in medicaments.
  • Another object of the present invention are therefore medicaments containing at least one compound of the general formula I according to the invention and optionally physiologically acceptable excipients.
  • the medicaments according to the invention are preferably suitable for controlling pain (in particular chronic pain, neuropathic pain, inflammatory pain), migraine, fibromyalgia or for the treatment of depression (unipolar, severe depression with and without delusion, moderate depression, mild depression, melancholia, bipolar depression; Bipolar disease I (mania and major depression), bipolar disease II (hypomania and major depression), cyclothymic personality disorders (hypomania and mild depression), subtypes), anxiety disorders (subtypes: generalized anxiety disorders, panic attacks, obsessive syndromes, social anxiety disorder, phobias, PSTD), Sleep disorders, urinary incontinence (stress and urgency), eating disorders, bulemia, attention deficit hyperactivity disorder, addiction and addiction, trichotillomania, neuroleptic and memory disorders.
  • the medicaments according to the invention can be in the form of liquid, semisolid or solid dosage forms, for example in the form of injection solutions. Drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, pave, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, are present and administered as such become.
  • the medicaments according to the invention usually comprise further physiologically tolerated pharmaceutical excipients, which are preferably selected from the group consisting of carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants, lubricants, lubricants, Flavors and binders.
  • physiologically tolerated pharmaceutical excipients are preferably selected from the group consisting of carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants, lubricants, lubricants, Flavors and binders.
  • physiologically acceptable excipients depend on whether the drug is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, mucous membranes and on the eyes, to be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, readily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.
  • Compounds of the general formula I according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration-promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable Forms of preparation may release the compounds of general formula I according to the invention also delayed.
  • the amount of the respective saturated or unsaturated heteroarylcycloalkylmethylamines of the general formula I according to the invention to be administered to the patient can vary and depends, for example, on the weight or age of the patient and on the mode of administration, the indication and the severity of the disease. Usually, 0.005 to 500 mg / kg, preferably 0.05 to 5 mg / kg body weight of the patient of at least one compound of the general formula I according to the invention are administered.
  • the stationary phase used for the column chromatography was silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt.
  • ether means diethyl ether.
  • the resulting crude product (3.25 g) was dissolved in 25 ml of absolute ethanol and 8 ml of ethyl acetate and treated successively with 4.1 ml of chlorotrimethylsilane and 0.58 ml of water.
  • the precipitated solid (1.84 g) was filtered off with suction (see Example 79), the mother liquor basified with dilute sodium hydroxide solution (2 mol / l), extracted repeatedly with a mixture of equal volumes of tetrahydrofuran and ethyl acetate, and the combined extracts dried over magnesium sulfate , filtered and concentrated.
  • the resulting residue (1.45 g) was chromatographed on silica gel with methanol to which 0.05% by volume aqueous ammonia solution (25% by mass) was added.
  • the product fraction (0.52 g) was dissolved in 50 ml of ethyl acetate and 0.66 ml of chlorotrimethylsilane added followed by 92 ⁇ l of water.
  • 0.57 g of methyl (2-pyridin-3-yl-cyclohex-1-enylmethyl) amine hydrochloride was obtained.
  • Example 10 As described for Example 10 were also 1.37 g of benzylmethyl (2-pyridin-3-yl-cyclohex-2-enylmethyl) amine obtained in about 30 ml of acetone were dissolved and transferred with 1.86 .mu.l of water and 1.30 ml of chlorotrimethylsilane in the corresponding hydrochloride.
  • the main fraction (7.83 g) was dissolved in about 80 ml of ethanol and with 2.2 molar equivalents of chlorotrimethylsilane and water in the hydrochloride of cis-3-dimethylaminomethyl-4-pyridin-3-yl-tetrahydrothiopyran-4-ol with a Melting point of 262-263 ° C converted.
  • the main fraction (3.70 g) was dissolved in about 40 ml of ethanol and treated with 2.2 molar equivalents of chlorotrimethylsilane and water in the hydrochloride of cis-3-dimethylaminomethyl- 4-pyridin-3-yltetrahydropyran-4-ol hydrochloride having a melting point of 276-277 ° C.
  • NA reuptake: Km 0.32 ⁇ 0.11 ⁇ M
  • IC 50 values are obtained, which are calculated according to the "Cheng-Prusoff equation” (US Pat. Cheng, YC and Prusoff, WH, 1973. Biochem. Pharmacol. 22, 3099-3108 ) in inhibitor constants (K i ) can be converted.
  • the IC 50 values were obtained using the computer program " Figure P” (Version 6.0, Biosoft, Cambridge, England). Km values were calculated according to Lineweaver, H. and Burk, D. (1934, J. Am. Chem. Soc. 56, 658-666 ). To represent K D values, the computer program “Ligand” (Version 4, Biosoft, England) has been used.
  • the formalin test ( Dubuisson, D. and Dennis, SG, 1977, Pain, 4, 161-174 ) represents a model for both acute and chronic pain. In the studies presented here, the chronic pain component was evaluated.
  • a one-time Formalln injection into the dorsal side of a hind paw induces a biphasic nociceptive reaction in free-moving experimental animals, which is detected by observing three clearly distinguishable behavioral patterns.
  • Formalin with a volume of 20 ⁇ l and a concentration of 1%, is administered subcutaneously into the dorsal side of the right hind paw of each animal.
  • the behavioral changes that differ from the normal behavior are continuously monitored and recorded up to 60 minutes after formalin administration at subintervals of 3 min .
  • T 0 , T 1 , T 2 , T 3 respectively correspond to the time in seconds in which the animal exhibited the behavior 0, 1, 2, or 3.
  • the investigations for determining the antidepressant activity of the compounds of the formula I according to the invention were carried out in the forced swimming test (Porsolt test) on the mouse ( Porsolt, R. et al., Arch. Int. Pharmacodyn. Vol. 229, pp. 327-336, (1977) ).
  • Male mice (20-25 g body weight) were individually placed in a shallow pool of water for a period of 6 minutes, from which they could not escape and thus were forced to swim. After some time, the animals gave up their swimming attempts and went into immobility phase. The duration of the immobility phase was determined in the interval of 2 to 6 minutes after the introduction of the animal.
  • Substance and vehicle groups each comprise 10 animals.
  • mice were used for the testing.
  • the animals were separated from the mother and placed in an incubation cage with an internal temperature of about 34 ° C.
  • the animals were individually placed on a temperature-controlled platform (23cm x 23 cm, divided by a grid In fields of 2cm x 2cm, 19 ⁇ 1 ° C) a soundproof test chamber for a period of 30 sec.
  • the ultrasound vocalisations were recorded with a high frequency condenser microphone, filtered, amplified digitized and recorded and analyzed using commercial software.
  • only animals with default values of at least 6 vocalizations within 30 sec and a body weight of 3.5 to 5.5 g were used.
  • mice After subcutaneous (sc) drug or vehicle injection The animals were returned to the incubation cage for a period of 10 minutes and then placed one at a time on the temperature controlled plate of the test chamber for a period of 4 minutes. In addition to the number of vocalisations, traverses of the plate's grid and body rotations of the mice were examined to investigate the effects of substance on the locomotor activity or coordination. Changes in vocalization frequencies, screen crossings and body rotations were reported relative to the vehicle control. For anxiolytics, a reduction in the vocalization rate is described.
  • Example 1 For the compound according to Example 1, a significant reduction of the vocalization frequency was measured. After administration of this compound, no significant changes in screen crossings and body rotations were observed. Thus, a selective anxiolytic effect was determined without affecting the locomotion and coordination in the isolation-induced pup vocalisation test.
  • the results for the compound according to Example 1 and for venlafaxine and citalopram are shown in the three following tables.

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Abstract

La présente invention concerne des hétéroarylcycloalkylméthyl amines saturées et insaturées de formule générale (I) dans laquelle W est CH2, O, S, SO ou SO2 et n = 0 - 3, un procédé pour les préparer, des produits pharmaceutiques les contenant, et l'utilisation de ces composés pour la préparation de produits pharmaceutiques, ainsi qu'un procédé pour traiter des dépressions, des troubles d'anxiété et/ou des douleurs.

Claims (13)

  1. Hétéroarylcycloalkylméthylamines saturées et non saturées de formule générale I
    Figure imgb0011
     formule dans laquelle
    W représente CH2, Y étant alors choisi entre H ou Cl en même temps que X et Z représentent H,
    ou bien
    X et Y forment ensemble une liaison et Z représente H,
    ou bien
    Y et Z forment ensemble une liaison et X représente H,
    ou bien
    W représente 0, S, SO ou SO2, Y étant choisi entre H, OH, Cl en même temps que X et Z représentent H
    ou bien
    X et Y forment ensemble une liaison et Z représente H,
    ou bien
    Y et Z forment ensemble une liaison et X représente H,
    et n a une valeur de 0 à 3,
    R1 et R2 sont choisis indépendamment l'un de l'autre entre H, un reste alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C3 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste cycloalkyle en C3 à C7, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué, ou un hétérocycle correspondant dans lequel un atome de carbone du noyau est remplacé par S, O ou NR3,
    R3 étant choisi entre
    H, un reste alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C2 à C10, chacun non ramifié ou ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    un reste alkylaryle, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste alkylhétéroaryle, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué, un reste aryle, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    ou bien
    R1 et R2 forment ensemble un reste cycloalkyle en C3 à C7, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué, ou un hétérocycle correspondant dans lequel un atome de carbone du noyau est remplacé par S, O ou NR4,
    R4 étant choisi entre
    H, un reste alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C3 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué,
    et
    G est choisi entre un groupe pyridine-3-yle ou pyridine-4-yle et est non substitué ou substitué une ou plusieurs fois, au moins un reste hydrogène étant remplacé par F, Cl, Br, I, CN, CF3, NO2, un radical alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C3 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste cycloalkyle en C3 à C7, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3 ou non substitué, ou un hétérocycle correspondant dans lequel un atome de carbone du noyau est remplacé par S, O ou NR5, R5 étant choisi entre
    H, un radical alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C2 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    un groupe OR6, OC(O)R6, OC(S)R6, C(O)R6, C(O)OR6, C(S)R6, C(S)OR6, SR6, S(O)R6 ou S(O2)R6, R6 étant choisi entre
    H, un radical alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C2 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste cycloalkyle en C3 à C7, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; ou un hétérocycle correspondant dans lequel un atome de carbone du noyau est remplacé par S, O ou NR7, R7 étant choisi entre
    H, un radical alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C3 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    un reste alkylaryle, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste aryle ou hétéroaryle, chacun substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    un groupe NR8R9C(O)NR8R9 ou S(O2)NR8R9, où R8 et R9 sont choisis indépendamment l'un de l'autre entre
    H, un reste alkyle en C1 à C18, alcényle en C2 à C18 ou alcynyle en C3 à C18, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste cycloalkyle en C3 à C7, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué, ou un hétérocycle correspondant dans lequel un atome de carbone du noyau est remplacé par S, O ou NR10, R10 étant choisi entre
    H, un radical alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C3 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    un reste alkylaryle, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste aryle ou hétéroaryle, chacun substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    ou bien
    R8 et R9 forment ensemble un reste cycloalkyle en C3 à C7, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué, ou un hétérocycle correspondant dans lequel un atome de carbone du noyau est remplacé par S, O ou NR10, R10 étant choisi entre
    H, un radical alkyle en C1 à C10, alcényle en C2 à C10 ou alcynyle en C3 à C10, chacun ramifié ou non ramifié, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ;
    un reste alkylaryle, aryle ou hétéroaryle, chacun substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué,
    également sous forme de leurs racémates ; leurs énantiomères, leurs diastéréo-isomères, en particulier sous forme de mélanges de leurs énantiomères ou de leurs diastéréo-isomères ou d'un énantiomère ou d'un diastéréo-isomère individuel ainsi que de leurs bases libres ou d'un sel formé avec un acide physiologiquement acceptable, en particulier le chlorhydrate.
  2. Composés de formule générale I suivant la revendication 1, caractérisés en ce que W représente CH2 et n a une valeur de 0 à 3.
  3. Composés de formule générale I suivant la revendication 1, caractérisés en ce que W représente O, S, SO ou SO2 et n a une valeur de 0 à 3.
  4. Composés de formule générale I suivant la revendication 3, caractérisés en ce que W représente O ou S et n a une valeur de 0 à 3.
  5. Composés de formule générale I suivant l'une des revendications 1 à 4, caractérisés en ce que
    R1 et R2 sont choisis indépendamment l'un de l'autre entre H, un reste alkyle en C1 à C10, un reste alkylaryle, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué ; un reste alkylhétéroaryle, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué,
    ou bien
    R1 et R2 forment ensemble un reste cycloalkyle en C3 à C7, saturé ou non saturé, substitué une ou plusieurs fois par F, Cl, Br, I, NH2, SH ou OH, OCH3, ou non substitué,
    et le reste G est non substitué ou substitué par Cl, Br ou OR6, R6 représentant H ou un radical alkyle en C1 à C10.
  6. Composés de formule générale I suivant l'une des revendications 1, 2 et 5, ces composés étant choisis entre :
    Diméthyl-(2-pyridine-3-yl-cyclohex-1-énylméthyl)-amine et le dichlorhydrate correspondant (1)
    Méthyl-(2-pyridine-3-yl-cyclohéx-1-énylméthyl)-amine et le chlorhydrate correspondant (2)
    Diméthyl-(2-pyridine-3-yl-cyclohex-2-énylméthyl)-amine et le chlorhydrate correspondant (4)
    Diméthyl-(2-pyridine-3-yl-cyclohexylméthyl)-amine et le chlorhydrate correspondant ; diastéréo-isomère 1 (6)
    Diméthyl-(2-pyridine-3-yl-cyclohexylméthyl)-amine et le chlorhydrate correspondant ; diastéréb-isomère 2 (7)
    Benzyl-méthyl-(2-pyridine-3-yl-cyclohex-1-énylméthyl)-amine et le chlorhydrate correspondant (10)
    Benzyl-méthyl-(2-pyridine-3-yl-cyclohex-2-énylméthyl)-amine et le chlorhydrate correspondant (11)
    [2-chloro-2-(6-chloropyridine-3-yl)-cycloheptylméthyl]-diméthylamine et le chlorhydrate correspondant (13)
    (2-chloro-2-pyridine-3-yl-cyclohexylméthyl)-diméthylamine et le chlorhydrate correspondant (14)
    [2-chloro-2'-(6-chloropyridine-3-yl)-cyclohexylméthyl]-diméthylamine et le chlorhydrate correspondant (15)
    Mélange de [2-(4-bromo-6-chloropyridine-3-yl)-cyclohex-1-énylméthyl]-méthylamine et de [2-(4-bromo-6-chloropyridine-3-yl)-cyclohex-2-énylméthyl]-méthylamine et les chlorhydrates correspondants (20)
    Diméthyl-(2-pyridine-3-yl-cyclohept-1-énylméthyl)-amine et le chlorhydrate correspondant (23)
    Diméthyl-(2-pyridine-3-yl-cyclohept-2-énylméthyl)-amine et le chlorhydrate correspondant (24)
    Mélange de chlorhydrate de [2-(6-chloropyridine-3-yl)-cyclo-oct-1-énylméthyl]-diméthylamino et de chlorhydrate de [2-(6-chloropyridine-3-yl)-cyclo-oct-2-énylméthyl]-diméthylamine (25)
    Diméthyl-(2-pyridine-3-yl-cycloheptylméthyl)-amine et le chlorhydrate correspondant ; diastéréo-isomère 1 (26)
    Diméthyl-(2-pyridine-3-yl-cycloheptylméthyl)-amine et le chlorhydrate correspondant ; diastéréo-isomère 2 (27)
    Diméthyl-(2-pyridine-3-yl-cyclopent-1-énylméthyl)-amine et le chlorhydrate correspondant (28)
    Diméthyl-(2-pyridine-3-yl-cyclopent-2-énylméthyl)-amine et le chlorhydrate correspondant (29)
    Diméthyl-(2-pyridine-3-yl-cyclopentylméthyl)-amine et le chlorhydrate correspondant (31)
    Diméthyl-(2-pyridine-3-yl-cyclo-oct-1-énylméthyl)-amine et le chlorhydrate correspondant (32)
    Diméthyl-(2-pyridine-3-yl-cyclo-oct-2-énylméthyl)-amine et le chlorhydrate correspondant (33)
    Diméthyl-(2-pyridine-3-yl-cyclo-octylméthyl)-amine et le chlorhydrate correspondant (35)
    (2-chloro-2-pyridine-4-yl-cycloheptylméthyl)-diméthylamine et le chlorhydrate correspondant (36)
    Diméthyl-(2-pyridine-4-yl-cyclohept-2-énylméthyl)-amine et le chlorhydrate correspondant (37)
    Diméthyl-(2-pyridine-4-yl-cyclohept-1-énylméthyl)-amine et le chlorhydrate correspondant (38)
    Diméthyl-(2-pyridine-4-yl-cyclohex-1-énylméthyl)-amine et le chlorhydrate correspondant (39)
    Mélange de chlorhydrate de diméthyl-(2-pyridine-4-yl-cyclohex-1-énylméthyl)amine et de chlorhydrate de diméthyl-(2-pyridine-4-yl-cyclohex-2-énylméthyl)-amine (40)
    Diméthyl-(2-pyridine-4-yl-cyclo-oct-1-énylméthyl)-amine et le chlorhydrate correspondant (42)
    Diméthyl-(2-pyridine-4-yl-cyclopent-2-énylméthyl)-amine et le chlorhydrate correspondant (43)
    Diméthyl-(2-pyridine-4-yl-cyclopent-1-énylméthyl)-amine et le chlorhydrate correspondant (47)
    [2-(6-chloropyridine-3-yl)-cyclohept-2-énylméthyl]-diméthylamine et le chlorhydrate correspondant (48)
    [2-(6-chloropyridine-3-yl)-cyclohex-1-énylméthyl]-diméthylamine et le chlorhydrate correspondant (49)
    [2-(5-méthoxypyridine-3-yl)-cyclohex-1-énylméthyl]-diméthylamine et le chlorhydrate correspondant (54)
    [2-(5-méthoxypyridine-3-yl)-cyclohex-2-énylméthyl]-diméthylamine et le chlorhydrate correspondant (55)
    Mélange de chlorhydrate de [2-(5-méthoxypyridine-3-yl)-cyclohept-1-énylméthyl]-diméthylamine et de chlorhydrate de [2-(5-méthoxypyridine-3-yl)-cyclohept-2-énylméthyl]-diméthylamine (58)
    Mélange de chlorhydrate de 5-(2-diméthylaminométhylcyclohept-1-ényl)-pyridine-3-ol et de chlorhydrate de 5-(7-diméthylaminométhyl-cyclohept-1-ényl)-pyridine-3-ol (59)
    [2-(5-méthoxypyridine-3-yl)-cycloheptylméthyl]-diméthylamine et le chlorhydrate correspondant (60)
    [2-(5-méthoxypyridine-3-yl)-cyclohexylméthyl]-diméthylamine et le chlorhydrate correspondant (62)
    Mélange de 2-(5-méthoxypyridine-3-yl)-cycloliexylméthyl]-diméthylamine (diastéréo-isomère 1) et de [2-(5-méthoxypyridine-3-yl)-cyclohexylméthyl]-diméthylamine (diastéréo-isomère 2) et des chlorhydrates correspondants (63)
    5-(2-diméthylaminométhyl-cyclohex-1-ényl)-pyridine-3-ol et le chlorhydrate correspondant (64)
    Dipropyl-(2-pyridine-3-yl-cyclohex-1-énylméthyl)-amine et le chlorhydrate correspondant (65)
    Dipropyl-(2-pyridine-3-yl-cyclohex-2-énylméthyl)-amine et le chlorhydrate correspondant (66)
    Chlorhydrate de [2-(5-méthoxypyridine-3-yl)-cyclo-oct-1-énylméthyl]-diméthylamine et [2-(5-méthoxypyridine-3-yl)-cyclo-oct-2-énylméthyl]-diméthylamine et les chlorhydrates correspondants (67)
    [2-(6-chloropyridine-3-yl)-cyclohex-1-énylméthyl]-diméthylamine et le chlorhydrate correspondant (68)
    [2-(6-chloropyridine-3-yl)-cyclohex-2-énylméthyl]-diméthylamine et le chlorhydrate correspondant (69)
    [2-(5-méthoxypyridine-3-yl)-cyclo-octylméthyl]-diméthylamine et le chlorhydrate correspondant ; diastéréo-isomère 1 (70)
    [2-(6-chloropyridine-3-yl)-cyclo-oct-2-énylméthyl]-diméthylamine et le chlorhydrate correspondant (71)
    [2-(5-méthoxypyridine-3-yl)-cyclo-octylméthyl]-diméthylamine et le chlorhydrate correspondant ; diastéréo-isomère 2 (72)
    [2-(5-méthoxypyridine-3-yl)-cyclo-oct-2-énylméthyl]-diméthylamine et le chlorhydrate correspondant (73)
    [2-(5-méthoxypyridine-3-yl)-cyclo-oct-1-énylméthyl]-diméthylamine et le chlorhydrate correspondant (74)
    5-(7-diméthylaminométhyl-cyclohept-1-ényl)-pyridine-3-ol et le chlorhydrate correspondant (75)
    5-(2-diméthylaminométhyl-cyclohept-1-ényl)-pyridine-3-ol et le chlorhydrate correspondant (76)
    5-(2-diméthylaminométhyl-cycloheptyl)-pyridine-3-ol et le chlorhydrate correspondant (77)
    Méthyl-(2-pyridine-3-yl-cyclohex-2-énylméthyl)-amine et le chlorhydrate correspondant (79).
  7. Composé de formule générale I suivant l'une des revendications 1, 3, 4 et 5, les composés étant choisis entré :
    3-diméthylaminométhyl-4-pyridine-3-yl-tétrahydrothiopyranne-4-ol et le chlorhydrate correspondant ; diastéréo-isomère 1 (50)
    3-diméthylaminométhyl-4-pyridine-3-yl-tétrahydrothiopyranne-4-ol et le chlorhydrate correspondant ; diastéréo-isomère 2 (51)
    3-diméthylaminométhyl-4-pyridine-3-yl-tétrahydropyranne-4-ol et le chlorhydrate correspondant (52)
    Diméthyl-(4-pyridine-3-yl-5,6-dihydro-2H-pyranne-3-yl-méthyl)-amine et le chlorhydrate correspondant (53).
  8. Procédé de production de composés de formule générale I ainsi que de leurs sels pharmaceutiquement acceptables, caractérisé en ce que des cycloalcanones de formule générale II sont amenées à réagir avec des sels d'immonium de formule III ou avec le paraformaldéhyde et une amine de formule IV, R10 ayant une définition analogue à celle de R1, et R11 ayant une définition analogue à celle de R2, les bases de Mannich obtenues sont amenées à réagir avec un composé organométallique de formule V, dans laquelle Z représente Li et V a une définition correspondant à G, dans des solvants entre - 70°C et 60°C, le composé organique de lithium de formule V, dans laquelle Z représente Li et V a une définition correspondant à G, étant préparé par réaction de composés halogénés de formule VI, dans laquelle A représente Cl, Br ou I et V a une définition correspondant à G, avec avantageusement une solution de n-butyllithium dans l'hexane par échange halogène-lithium, ce qui permet d'obtenir des produits de formule générale VII dans laquelle R10 a une définition analogue à celle de R1, R11 a une définition analogue à celle de R2 et V a une définition correspondant à G, qu'on fait réagir avec le chlorure de thionyle et qu'on traite ensuite dans des conditions basiques pour obtenir un mélange de composés de formules générales VIII, IXa et IXb dans lesquelles R10 a une définition analogue à celle de R1, R11 a une définition analogue à celle de R2 et V a une définition correspondant à G, on sépare les composés, on effectue ensuite l'hydrogénation des composés de formules générales IXa et IXb avec de l'hydrogène catalytiquement activé, en utilisant comme catalyseur le platine ou le palladium absorbé sur une matière de support, dans des solvants à des pressions de 0,1 à 10 bars et à des températures de 20°C à 80°C pour obtenir des composés de formule X dans laquelle R10 a une définition analogue à celle de R1, R11 a une définition analogue à celle de R2 et V a une définition correspondant à G.
  9. Procédé suivant la revendication 8, caractérisé en ce qu'au moins un groupe OH contenu dans la formule I est remplacé par un groupe OSi(Ph)2tertiobutyle, au moins un groupe SH est remplacé par un groupe S-p-méthoxybenzyle et/ou au moins un groupe NH2 est remplacé par un groupe NO2 et, après la fin de la séquence réactionnelle totale, un groupe OSi(Ph)2tertiobutyle est éliminé avec le fluorure de tétrabutylammonium dans le tétrahydrofuranne et/ou au moins un groupe p-méthoxybenzyle est éliminé avec un dérivé métallique d'amine, avantageusement un dérivé sodique d'amine et/ou au moins un groupe NO2 est réduit en un groupe NH2.
  10. Procédé suivant les revendications 8 et 9, caractérisé en ce que, après la réaction avec BuLi, un produit du procédé portant au moins un groupe C(O)OCH3 et/ou un groupe C(S)OCH3 est saponifié avec une solution de KOH ou une solution de NaOH dans du méthanol à une température de 40 à 60°C.
  11. Médicament, contenant au moins un composé de formule générale I ou l'un de ses sels pharmaceutiquement acceptables.
  12. Utilisation d'un composé de formule générale I ou de l'un de ses sels pharmaceutiquement acceptables pour la préparation d'un médicament destiné au traitement de dépressions, d'angoisses et/ou de douleurs.
  13. Composition pharmaceutique qui contient au moins un composé de formule générale I ou l'un de ses sels pharmaceutiquement acceptables ainsi qu'au moins une substance pharmaceutique auxiliaire.
EP03815065A 2002-12-20 2003-12-19 Heteroarylcycloalkymethyl amines saturees et insaturees en tant qu'antidepresseurs Expired - Lifetime EP1572653B1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
SI200331099T SI1572653T1 (sl) 2002-12-20 2003-12-19 Nasiceni in nenasiceni heteroarilcikloalkilmetil-amini kot antidepresivi
CY20081100091T CY1107867T1 (el) 2002-12-20 2008-01-25 Κεκορεσμενες και ακορεστες ετεροαρυλοκυκλοαλκυλομεθυλαμινες σαν αντικαταθλιπτικα

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DE10261091 2002-12-20
DE10261091A DE10261091A1 (de) 2002-12-20 2002-12-20 Gesättigte und ungesättigte Heteroarylcycloalkylmethyl-Amine
PCT/EP2003/014653 WO2004063161A1 (fr) 2002-12-20 2003-12-19 Heteroarylcycloalkymethyl amines saturees et insaturees en tant qu'antidepresseurs

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EP1572653A1 EP1572653A1 (fr) 2005-09-14
EP1572653B1 true EP1572653B1 (fr) 2007-11-21

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US (1) US7384961B2 (fr)
EP (1) EP1572653B1 (fr)
JP (1) JP2006523182A (fr)
AU (1) AU2003296693A1 (fr)
CA (1) CA2509072C (fr)
CY (1) CY1107867T1 (fr)
DE (2) DE10261091A1 (fr)
DK (1) DK1572653T3 (fr)
ES (1) ES2295699T3 (fr)
PL (1) PL377528A1 (fr)
PT (1) PT1572653E (fr)
WO (1) WO2004063161A1 (fr)

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DE602007003024D1 (de) * 2006-06-27 2009-12-10 Sandoz Ag Neues verfahren zur salzherstellung
US10653681B2 (en) 2016-03-16 2020-05-19 Recurium Ip Holdings, Llc Analgesic compounds

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GB765874A (en) * 1953-12-21 1957-01-16 Wellcome Found Improvements in or relating to methods of preparing chemical compounds containing the pyrrocoline nucleus and new chemical compounds produced thereby
US4021560A (en) * 1975-08-11 1977-05-03 American Home Products Corporation 2-[(Dimethylamino)(3-pyridyl)methyl]cyclohexanol and related compounds
IE56001B1 (en) * 1982-09-30 1991-03-13 Boots Co Plc 1-arylcyclobutylmethylamine compounds
DE19609847A1 (de) * 1996-03-13 1997-09-18 Gruenenthal Gmbh Dimethyl-(3-aryl-but-3-enyl)-aminverbindungen als pharmazeutische Wirkstoffe
DE19857475A1 (de) * 1998-12-14 2000-06-15 Gruenenthal Gmbh Substituierte Cycloheptene, deren Herstellung und Verwendung
DE10049481A1 (de) * 2000-09-29 2002-05-02 Gruenenthal Gmbh Substituierte C-Cyclohexylmethylamin-Derivate
GB2367554A (en) * 2000-10-04 2002-04-10 Lilly Co Eli Pharmacologically active amines

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DK1572653T3 (da) 2008-02-18
JP2006523182A (ja) 2006-10-12
US7384961B2 (en) 2008-06-10
ES2295699T3 (es) 2008-04-16
US20060025456A1 (en) 2006-02-02
CA2509072C (fr) 2011-11-08
EP1572653A1 (fr) 2005-09-14
PT1572653E (pt) 2007-12-14
CA2509072A1 (fr) 2004-07-29
PL377528A1 (pl) 2006-02-06
CY1107867T1 (el) 2013-06-19
AU2003296693A1 (en) 2004-08-10
WO2004063161A1 (fr) 2004-07-29
DE50308666D1 (de) 2008-01-03
DE10261091A1 (de) 2004-07-01

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